Metals in Brain Tissue in Alzheimer's Disease

The good (copper), the bad (iron) and the ugly (aluminium)

In 2014 I published an opinion article in which I made the case that at the very least aluminium in brain tissue contributes towards earlier onset and more aggressive forms of Alzheimer's disease. At that time I formed the hypothesis that for aluminium to be THE major player in Alzheimer’s disease (AD) we would expect to find high concentrations of aluminium in brain tissue of individuals who died with a diagnosis of familial Alzheimer’s disease (fAD). This is a rare form of Alzheimer’s disease characterised by an earlier age of onset and significant linkage to certain specific genetic mutations associated with metabolism of the amyloid precursor protein (APP).

In 2016 the London Brain Bank provided us with brain tissue from 12 individuals who died with a diagnosis of fAD. In 2017 we published the first data on the aluminium content of brain tissue in fAD. The data were intriguing to say the least and proved my working hypothesis that the aluminium content of brain tissue in fAD would be elevated. These unique, at that time, data of aluminium in brain tissue in fAD raised the spectre of aluminium as a cause of AD but, could they be repeated.

In 2019 we received brain tissue from a Columbian cohort of individuals who died with a diagnosis of fAD. I have copied a table of the data obtained below.

The data from this seminal paper left me in no doubt. Aluminium in brain tissue is the cause of Alzheimer’s disease. The exceptional images of aluminium co-deposited with amyloid beta protein in senile plaques (see paper) added further weight to my conclusion.

Before my untimely removal from academia in 2021 I was able to complete measurements for iron and copper in brain tissue in this Colombian cohort of fAD. To my knowledge these are the only measurements, as per aluminium, of iron and copper in brain tissue in fAD. Unfortunately I did not have the opportunity to submit these data for publication in a peer-reviewed journal. To this end and in appreciation of the unique importance of these data I have decided to publish them herein.

Bearing in mind my limits as a statistician I asked my colleague Dr Beth Clarkson (see our seminal paper) to carry out the statistical analyses on the data.

Below I am presenting the summary tables for copper and iron.

All data are microgram/g (or ppm) dry wt.

The control data are those described in this paper. Data defined as sporadic AD (sAD) are taken from our previously published paper in the journal Metallomics.

Anyone interested in serious further analyses of these data for copper and iron may request the Excel file.

So, what did we find.

Copper

There were no statistically significant (P>0.05) differences between any of the brain regions ( F - frontal, O - occipital, P - parietal, T - temporal) for any of the 3 (Control, fAD, sAD) data sets.

For whole brains the mean for sAD was significantly (P<0.05) lower than Control but not significantly different to fAD. The means for fAD and sAD were not significantly different.

Iron

There were no statistically significant (P>0.05) differences between any of the brain regions ( F - frontal, O - occipital, P - parietal, T - temporal) for any of the 3 (Control, fAD, sAD) data sets.

For whole brains the means for both sAD and fAD were significantly (P<0.05) higher than the mean for the Control brain tissues.

Essentially the unique data for fAD brains confirms previous suggestions that copper may be protective against AD while iron exacerbates the disease. This relationship between aluminium, iron and copper in brain tissue and AD is almost certainly indicative of a role for oxidative damage in brain tissue in AD. Iron is of course redox active, while aluminium is a potent prooxidant and copper an important antioxidant. I intend to write future musings on this important relationship in AD.

Dr Clarkson and I are happy to share these unique data with you. They are, we believe, important. Dr Clarkson has completed a full statistical analysis of the data and we are only presenting the headline findings herein. Any scientist wishing to access the full data set can do so by requesting such.

When I began Dr’s Newsletter I promised to share with you my many musings on the subject of aluminium and human disease. Herein, as with previous substack posts, I am sharing unique and valuable scientific data, data that are not available elsewhere. In this instance, the good (copper), the bad (iron) and the ugly (aluminium) of metal involvement in the aetiology of Alzheimer’s disease.